Iain A. McNeish, MD, PhD
Treatment with the PARP inhibitor rucaparib demonstrated robust clinical activity and a tolerable safety profile for women with biomarker-defined relapsed ovarian cancer, according to results from the phase II ARIEL2 study presented at the 2015 ASCO Annual Meeting.
In the study, the objective response rate (ORR) by RECIST or CA-125 was 82% in patients with BRCA
-mutated ovarian cancer and 45% in a BRCA
-like group defined by a distinct biomarker associated with homologous recombination deficiency (HRD). In the biomarker negative arm of the study, the ORR by RECIST was 13% and 21% with CA-125.
"Rucaparib is highly active and well tolerated treatment for patients with BRCA mutated tumors, with an objective response rate in excess of 80% in both germline and somatic mutant tumors," lead investigator Iain A. McNeish, MD, PhD, professor of Gynecological Oncology at the Institute of Cancer Sciences, University of Glasgow, said during his presentation. "This is the first clinical study to demonstrated prospectively that the genome scarring HRD signature can identify BRCA wild-type tumors that will benefit from rucaparib."
The biomarker assay for rucaparib explored in the ARIEL2 study was based on next-generation sequencing, with the theory that HRD causes genomic "scarring" that can be quantified using genome-wide loss of heterozygosity (LOH) in single-nucleotide polymorphisms. On this basis, the biomarker panel was compiled through an analysis of mutations associated with HRD and LOH that could predict sensitivity to rucaparib.
"Defining a genomic scarring cutoff is challenging because genomic damage is not a binary event it is a continuous variable," McNeish said. "However, by mining publically available datasets–TCGA and AOCS in particular–we've been able to identify an optimal genomic LOH cutoff and we've prospectively tested that in the ARIEL2 study."
In the phase II study, 204 women with high-grade serous or endometrioid ovarian cancer were treated with rucaparib at 600 mg twice daily. Patients were stratified into three arms, based on BRCA
mutation and biomarker status. Only 15 patients with known germline BRCA
mutations were enrolled. Overall, 20% of patients had a BRCA
mutation (n = 41), 40% were BRCA
-like (biomarker positive; n = 82), 34% had biomarker-negative disease (n = 69), and 6% were unclassified (n = 12).
The median age of patients enrolled was 65 years and the majority had epithelial ovarian cancer (80%) with serous histology (96%). Fifty-seven percent of patients had received 1 prior therapy and 43% had received â‰¥2 prior regimens. The primary endpoint of the study was progression-free survival (PFS), with ORR, safety, and pharmacokinetics as secondary outcome measures.
The median PFS was 9.4 months (90% CI, 7.3-not reached) in the BRCA
-mutated group and 7.1 months in the BRCA
-like arm (90% CI, 3.7-10.8). In the biomarker negative group, the median PFS was 3.7 months (90% CI, 3.5-5.5).
In comparison with the negative group, those with a BRCA
mutation saw a 53% reduction in the risk of progression with rucaparib (HR = 0.47; 90%, 0.35-0.64). For those with a BRCA
-like tumor, the risk of progression was reduced by 39% compared with the negative biomarker arm (HR = 0.61; 90% CI, 0.41-0.92).
There were robust responses in both the somatic and germline mutation carriers with rucaparib. In those with germline mutations in BRCA
, the ORR by RECIST or CA-125 was 81%. In patients with somatic BRCA
mutations, the ORR reached 88%, which included 4 complete responses. By RECIST alone, the ORR was 69% in the mutated group and 30% in the biomarker-positive arm.Â The median duration of response was 9.3 months and remained ongoing at the analysis.Â
"Since this data cut, we've now had two further complete responses, one in a germline mutation carrier and another in a patient with BRCA
-like phenotype," McNeish noted.Â
The most frequently observed adverse events with rucaparib were nausea (66%), asthenia/fatigue (61%), ALT/AST increase (40%), dysgeusia (38%), and decreased appetite (31%). The most common grade 3/4 adverse events were anemia (16%), ALT/AST increase (11%), and fatigue (6%).
"Rucaparib is generally well tolerated, and we saw no cases of myelodysplasia or AML in any of the patients," McNeish said. "The increase in AST/ALT was transient and responded spontaneously and was not associated with other features of liver toxicity."
Part 2 of the ARIEL2 study remains ongoing for patients with heavily pretreated ovarian cancer. Clovis Oncology, the company developing rucaparib, plans to submit a new drug application (NDA) to the FDA in 2016, based on data from this expansion cohort.
“With these data presented at ASCO, we believe rucaparib has clearly emerged as a unique and best-in-class PARP inhibitor," Patrick J. Mahaffy, president and CEO of Clovis Oncology, said in a statement. "With the ARIEL2 extension enrolling rapidly, we look forward to submitting our NDA for rucaparib for the treatment of advanced ovarian cancer next year."
In April 2015, rucaparib received a breakthrough therapy designation from the FDA as a treatment for women with BRCA
-mutated advanced ovarian cancer following progression on at least two prior lines of platinum-based chemotherapy. In addition to the phase II study, the phase III ARIEL3 trial will randomize patients with platinum-sensitive, high-grade ovarian cancer to maintenance therapy with rucaparib or placebo. The study plans to enroll 540 patients, with enrollment expected to complete within the next year.
McNeish IA, Oza AM, Coleman RL, et al. Results of ARIEL2: A phase 2 trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis. J Clin Oncol. 2015;33 (suppl; abstr 5508).